Rieche et al. (Arch. Pharmaz. 293, 957 (1960) and 296, 770(1963) disclose the antifungal properties of 3-(phenylalkyl)tetrahydro-2H-1,3,5-thiadiazine-2-thiones. In (Arzneimittel Forschung, 19, 1807 (1969), Schorr et al. report that they prepared certain derivatives of tetrahydro-2H-1,3,5-thiadiazine-2-thione and conducted various chemotherapeutic studies with many of these compounds. These studies indicate that tetrahydro-2H-1,3,5-thiadiazine-2-thiones possess antifungal and antibacterial activity. Interestingly, Schorr et al. also found that derivatives of tetrahydro-2H-1,3,5-thiadiazine-2-thiones containing heteroaromatic substituents are markedly less active than the corresponding compounds in which the heteroaromatic ring has been replaced by an aromatic ring. For instance, replacement of a pyridylmethyl group with benzyl in said derivatives will significantly increase the biological activity.
It has been unexpectedly found that certain 5-substituted-tetrahydro-3(4-pyridylmethyl)-2H-1,3,5-thiadiazine-2-thiones are highly effective fungicides characterized by markedly low phytotoxicity.
The 3-(4-pyridylmethyl)-tetrahydro-2H-1,3,5-thiadiazine-2-thione compounds of the present invention are represented by formula (I): ##STR1## wherein R is a member selected from the group consisting of alkyl C.sub.1 -C.sub.12, hydroxyethyl, --CH.sub.2 COOH, --CH.sub.2 COONa, --CH.sub.2 CONH.sub.2 and the radical ##STR2## wherein X is selected from the group consisting of hydrogen, hydroxy and chloro, Y is hydrogen or methyl. The compounds are useful for the control of pathogenic fungi of agricultural crops being especially effective for the control of rice blast, tomato late blight, and apple scab.
Preferred compounds for the control of pathogenic fungi of agricultural crops are those of the above formula (I) wherein R is a member selected from the group consisting of methyl, ethyl, isopropyl, n-butyl, t-butyl, n-dodecyl, .beta.-hydroxyethyl, ##STR3## and 4-chloro-o-tolyl.
Illustrative of a method for preparing the compounds of the present invention involves reacting approximately equimolar amounts of 4-(aminomethyl)pyridine and carbon disulfide in aqueous acetonitrile in the presence of a one molar equivalent of an alkali metal hydroxide, such as sodium hydroxide or potassium hydroxide, at a temperature from about 15.degree. C. to about 30.degree. C. for a period from about one to three hours. There is then obtained the corresponding pyridylmethyldithiocarbamate of formula (II) as graphically illustrated hereinbelow: ##STR4## Next, the so-obtained dithiocarbamate is reacted with an aqueous solution of two molar equivalents of formaldehyde and an aqueous solution of a one molar equivalent of the appropriate R-NH.sub.2 amine acid salt to yield the desired formula (I) tetrahydro-2H-1,3,5-thiadiazine-2-thione as graphically illustrated below: ##STR5## wherein R is as defined hereinabove.
In general, the fungicidal method of control of the present invention involves applying a fungicidally effective amount of a formula (I) compound to the foliage of agricultural crops where control of phytopathogenic fungi is desired. Application of a formula (I) tetrahydro-2H-1,3,5-thiadiazine-2-thione compound at a rate of from about 0.04 kg to about 8.96 kg per hectare and, preferably, from about 0.09 kg to about 4.48 kg per hectare is usually sufficient to achieve satisfactory control of said fungi without significant phytotoxic damage to the host crops.
Advantageously, the novel tetrahydro-2H-1,3,5-thiadiazine-2-thione compounds of the present invention represented by formula (I) above may be formulated as liquid or emulsifiable concentrates, wettable powders, dusts, dust concentrates and the like by well-known and commercially accepted methods.
Liquid and/or emulsifiable concentrates may be conveniently prepared by dissolving the appropriate formula (I) compound in amounts of about from 5% to 95% by weight and, preferably, 15% to 75%, by weight, in a solvent selected from the group consisting of water: C.sub.1 -C.sub.4 aliphatic alcohols; ketones such as acetone, methyl ethyl ketone, methyl butyl isobutyl ketone, or cyclohexanone and the like; aromatic hydrocarbons such as benzene, toluene and xylene, aromatic petroleum distillates, or mixtures thereof. Additionally, 1 to 5% by weight of a surfactant, e.g. a polyoxyethylene sorbitan monolaurate surfactant or the like is incorporated into the above formulation. Application of the material is made by adding a predetermined quantity of the above concentrate as such or in combination with an additional quantity of water or another suitable inert solvent, e.g. deodorized kerosene.
Wettable powders can be prepared by milling and blending together between about 25% to 85% by weight of a compound of formula (I), a solid carrier such as attapulgite, kaolin, diatomaceous earth, silica and the like and about 1% to 5% by weight of a dispersing or wetting agent or mixtures thereof, such as sodium lignin sulfonate, N-methyl-N-oleoyltaurate and the like. In the above formulations the amount of solid carrier used is variable and obviously its value given in percent, by weight, is dependent on the amount of active ingredient and dispersing or wetting agent chosen for that particular formulation.
Dusts are generally prepared by blending and milling together from about 0.5% to 20%, by weight, of a tetrahydro-2H-1,3,5-thiadiazine-2-thione of formula (I) with an inert diluent such as an attapulgite type of clay, kaolin, diatomaceous earth, talc, fuller's earth and the like. Preferably, the dust contains from about 5% to 10%, by weight, of active ingredient and about 95% to 90%, by weight, of said inert diluent.
Dust concentrates are prepared similarly except that they contain usually from about 25% to 75% by weight of active ingredient and from 75% to 25% by weight of diluent.
The above formulations containing the appropriate formula (I) compounds of the present invention may be applied to the foliage of the agricultural crops to be protected by commercially available spraying and dusting equipment. For spraying, liquid or emulsifiable concentrates and wettable powders are diluted with water or another suitable inert solvent, such as deodorized kerosene, and applied as spray preparations of 100 ppm to 4800 ppm; or 0.090 kg to 4.48 kg per hectare.